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Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury

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Abstract

Cannabidiol (CBD), a non-psychoactive constituent of cannabis, has been reported to induce neuroprotective effects in several experimental models of brain injury. We aimed at investigating whether this drug could also improve locomotor recovery of rats submitted to spinal cord cryoinjury. Rats were distributed into five experimental groups. Animals were submitted to laminectomy in vertebral segment T10 followed or not by application of liquid nitrogen for 5 s into the spinal cord at the same level to cause cryoinjury. The animals received injections of vehicle or CBD (20 mg/kg) immediately before, 3 h after and daily for 6 days after surgery. The Basso, Beattie, and Bresnahan motor evaluation test was used to assess motor function post-lesion one day before surgery and on the first, third, and seventh postoperative days. The extent of injury was evaluated by hematoxylin-eosin histology and FosB expression. Cryogenic lesion of the spinal cord resulted in a significant motor deficit. Cannabidiol-treated rats exhibited a higher Basso, Beattie, and Bresnahan locomotor score at the end of the first week after spinal cord injury: lesion + vehicle, day 1: zero, day 7: four, and lesion + Cannabidiol 20 mg/kg, day 1: zero, day 7: seven. Moreover, at this moment there was a significant reduction in the extent of tissue injury and FosB expression in the ventral horn of the spinal cord. The present study confirmed that application of liquid nitrogen to the spinal cord induces reproducible and quantifiable spinal cord injury associated with locomotor function impairments. Cannabidiol improved locomotor functional recovery and reduced injury extent, suggesting that it could be useful in the treatment of spinal cord lesions.

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References

  • Bamber N, Li H, Lu X, Oudega M, Aebischer P, Xu X (2001) Neurotrophins BDNF and NT-3 promote axonal re-entry into the distal host spinal cord through Schwann cell-seeded mini-channels. Eur J Neurosci 13:257–268

    PubMed  CAS  Google Scholar 

  • Basso M, Beattie S, Bresnahan C (1995) A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 12:1–21

    Article  PubMed  CAS  Google Scholar 

  • Basso M, Beattie S, Bresnahan C (1996a) Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol 139:244–256

    Article  PubMed  CAS  Google Scholar 

  • Basso M, Beattie S, Bresnahan C, Anderson K, Faden I, Gruner A, Holford R, Hsu Y, Noble J, Nockels L, Perot L, Salzman K, Young W (1996b) MASCIS evaluation of open field locomotor scores: effects of experience and teamwork on reliability. J Neurotrauma 13:343–359

    Article  PubMed  CAS  Google Scholar 

  • Beattie S, Bresnahan C, Komon J, Tovar A, Van Meter M, Anderson K, Faden I, Hsu Y, Noble J, Salzman S, Young W (1997) Endogenous repair after spinal cord contusion injuries in the rat. Exp Neurol 148:453–463

    Article  PubMed  CAS  Google Scholar 

  • Braida D, Pegorini S, Arcidiacono V, Consalez G, Croci L, Sala M (2003) Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett 346:61–64

    Article  PubMed  CAS  Google Scholar 

  • Carlson D, Gorden D, Oliff S, Pillai J, Lamanna C (2003) Sustained spinal cord compression: part I: time-dependent effect on long-term pathophysiology. J Bone Joint Surg Am 85-A:86–94

    PubMed  Google Scholar 

  • Carrier J, Auchampach A, Hillard J (2006) Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci USA 103:7895–7900

    Article  PubMed  CAS  Google Scholar 

  • Castillo A, Tolón M, Fernández-Ruiz J, Romero J, Martinez-Orgado J (2010) The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis 37:434–440

    Article  PubMed  CAS  Google Scholar 

  • Chen JF, Sonsalla PK, Pedata F, Melani A, Domenici MR, Popoli P, Geiger J, Lopes LV, de Mendonça A (2007) Adenosine A2A receptors and brain injury: broad spectrum of neuroprotection, multifaceted actions and “fine tuning” modulation. Prog Neurobiol 83(5):310–331

    Article  PubMed  CAS  Google Scholar 

  • Cheng H, Cao Y, Olson L (1996) Spinal cord repair in adult paraplegic rats: partial restoration of hind limb function. Science 273:510–513

    Article  PubMed  CAS  Google Scholar 

  • Collins H, West R, Parmely D, Samson M, Ward A (1986a) The histopathology of freezing injury to the rat spinal cord. A light microscope study. I. Early degenerative changes. J Neurophatol Exp Neurol 45(6):721–741

    Article  CAS  Google Scholar 

  • Collins GH, West NR, Parmely JD (1986b) The histopathology of freezing injury to the rat spinal cord. A light and electron microscope study. II. Repair and regeneration. J Neuropathol Exp Neurol 45(6):742–757

    Article  PubMed  CAS  Google Scholar 

  • Cunha J, Carlini A, Pereira E, Ramos O, Pimentel C, Gagliardi R, Sanvito L, Lander N, Mechoulam R (1980) Chronic administration of cannabidiol to healthy volunteers and epileptic patients. Pharmacology 21:175–185

    Article  PubMed  CAS  Google Scholar 

  • Del Bel E, Borges A, Defino L, Guimaraes S (2000) Induction of Fos protein immunoreactivity by spinal cord contusion. Braz J Med Biol Res 33:521–528

    Article  PubMed  CAS  Google Scholar 

  • Drysdale J, Platt B (2003) Cannabinoids: mechanisms and therapeutic applications in the CNS. Curr Med Chem 10:2719–2732

    Article  PubMed  CAS  Google Scholar 

  • El-Remessy B, Khalil E, Matragoon S, Abou-Mohamed G, Tsai J, Roon P, Caldwell B, Caldwell W, Green K, Liou I (2003) Neuroprotective effect of (-)Delta9-tetrahydrocannabinol and cannabidiol in N-methyl-d-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite. Am J Pathol 163:1997–2008

    Article  PubMed  CAS  Google Scholar 

  • Emery E, Aldana P, Bunge B, Puckett W, Srinivasan A, Keane W, Bethea J, Levi D (1998) Apoptosis after traumatic human spinal cord injury. J Neurosurg 89:911–920

    Article  PubMed  CAS  Google Scholar 

  • Esposito G, De Filippis D, Carnuccio R, Izzo A, Iuvone T (2006) The marijuana component cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt/beta-catenin pathway rescue in PC12 cells. J Mol Med 84:253–258

    Article  PubMed  CAS  Google Scholar 

  • Feng SQ, Kong XH, Guo SF, Wang P, Li L, Zhong JH, Zhou XF (2005) Treatment of spinal cord injury with co-grafts of genetically modified Schwann cells and fetal spinal cord cell suspension in the rat. Neurotox Res 7(1–2):169–177

    Article  PubMed  CAS  Google Scholar 

  • García-Arencibia M, González S, De Lago E, Ramos Á, Mechoulam R, Fernández-Ruiz J (2007) Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties. Brain Res 1134:162–170

    Article  PubMed  Google Scholar 

  • Guimarães S, Chiaretti M, Graeff G, Zuard W (1990) Antianxiety effect of cannabidiol in the elevated plus-maze. Psychopharmacology (Berl) 100:558–559

    Article  Google Scholar 

  • Hayakawa K, Mishima K, Nozako M, Ogata A, Hazekawa M, Liu X, Fujioka M, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M (2007a) Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52:1079–1087

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Mishima K, Nozako M, Hazekawa M, Irie K, Fujioka M, Orito K, Abe K, Hasebe N, Egashira N, Iwasaki K, Fujiwara M et al (2007b) Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J Neurochem 102(5):1488–1496

    Article  PubMed  CAS  Google Scholar 

  • Houweling A, van Asseldonk J, Lankhorst A, Hamers F, Martin D, Bär R, Joosten A (1998) Local application of collagen containing brain-derived neurotrophic factor decreases the loss of function after spinal cord injury in the adult rat. Neurosci Lett 251:193–196

    Article  PubMed  CAS  Google Scholar 

  • Hsu CY, Hogan EL, Gadsden RHS, Spicer KM, Shi MP, Cox RD (1985) Vascular permeability in experimental spinal cord injury. J Neurol Sci 70:275–282

    Article  PubMed  CAS  Google Scholar 

  • Iannotti CA, Clark M, Horn KP, van Rooijen N, Silver J, Steinmetz MP (2011) A combination immunomodulatory treatment promotes neuroprotection and locomotor recovery after contusion SCI. Exp Neurol 230(1):3–15

    Article  PubMed  CAS  Google Scholar 

  • Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo A (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89:134–141

    Article  PubMed  CAS  Google Scholar 

  • Izzo A, Borrelli F, Capasso R, Di Marzo V, Mechoulam R (2009) Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 30:515–527

    Article  PubMed  CAS  Google Scholar 

  • Jonat C, Rahmsdorf HJ, Park KK, Cato AC, Gebel S, Ponta H, Herrlich P (1990) Antitumor promotion and antiinflammation: down-modulation of AP-1 (Fos/Jun) activity by glucocorticoid hormone. Cell 62:1189–1204

    Article  PubMed  CAS  Google Scholar 

  • Jones L, Oudega M, Bunge M, Tuszynski M (2001) Neurotrophic factors, cellular bridges and gene therapy for spinal cord injury. J Physiol 533:83–89

    Article  PubMed  CAS  Google Scholar 

  • Karin M, Liu ZG, Zandi E (1997) AP-1 function and regulation. Curr Opin Cell Biol 9:240–246

    Article  PubMed  CAS  Google Scholar 

  • Kitada M, Mizoguchi A, Tohyama K, Ohtsubo A, Fujimoto E, Chakrabortty S, Ide C (1999) Comparison of the axonal and glial reactions between the caudal and rostral border in the cryoinjured dorsal funiculus of the rat spinal cord. Restor Neurol Neurosci 14(4):251–263

    PubMed  Google Scholar 

  • Lastres-Becker I, Molina-Holgado F, Ramos A, Mechoulam R, Fernández-Ruiz J (2005) Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis 19:96–107

    Article  PubMed  CAS  Google Scholar 

  • Leweke M, Schneider U, Radwan M, Schmidt E, Emrich H (2000) Different effects of nabilone and cannabidiol on binocular depth inversion in Man. Pharmacol Biochem Behav 66:175–181

    Article  PubMed  CAS  Google Scholar 

  • Liu Z, Xu M, Hu R, Du C, Zhang X, Mcdonald W, Dong X, Wu J, Fan S, Jacquin F, Hsu Y, Choi W (1997) Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 17:5395–5406

    PubMed  CAS  Google Scholar 

  • Ma M, Basso M, Walters P, Stokes T, Jakeman B (2001) Behavioral and histological outcomes following graded spinal cord contusion injury in the C57Bl/6 mouse. Exp Neurol 169:239–254

    Article  PubMed  CAS  Google Scholar 

  • McClung CA, Ulery PG, Perrotti LI, Zachariou V, Berton O, Nestler EJ (2004) DeltaFosB: a molecular switch for long-term adaptation in the brain. Brain Res Mol Brain Res 132(2):146–154

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R (2002) Discovery of endocannabinoids and some random thoughts on their possible roles in neuroprotection and aggression. Prostaglandins Leukot Essent Fatty Acids 66:93–99

    Article  PubMed  CAS  Google Scholar 

  • Menei P, Montero-Menei C, Whittemore S, Bunge R, Bunge M (1998) Schwann cells genetically modified to secrete human BDNF promote enhanced axonal regrowth across transected adult rat spinal cord. Eur J Neurosci 10:607–621

    Article  PubMed  CAS  Google Scholar 

  • Mishima K, Hayakawa K, Abe K, Ikeda T, Egashira N, Iwasaki K, Fujiwara M (2005) Cannabidiol prevents cerebral infarction via a serotonergic 5-Hydroxytryptamine 1A receptor-dependent mechanism. Stroke 36:1071–1076

    Article  CAS  Google Scholar 

  • Molander C, Xu Q, Rivero-Melian C, Grant G (1989) Cytoarchitectonic organization of the spinal cord in the rat: II. The cervical and upper thoracic cord. J Comp Neurol 289:375–385

    Article  PubMed  CAS  Google Scholar 

  • Nestler EJ (2008) Transcriptional mechanisms of addiction: role of DeltaFosB. Philos Trans R Soc Lond B Biol Sci 363(1507):3245–3255

    Article  PubMed  CAS  Google Scholar 

  • Pertwee G (2001) Cannabinoids receptors and pain. Prog Neurobiol 63:569–611

    Article  PubMed  CAS  Google Scholar 

  • Pertwee G (2005) Inverse agonism and neutral antagonism at cannabinoid CB1 receptors. Life Sci 12:1307–1324

    Article  Google Scholar 

  • Plemel R, Duncan G, Chen W, Shannon C, Park S, Sparling S, Tetzlaff W (2008) A graded forceps crush spinal cord injury model in mice. J Neurotrauma 25:350–370

    Article  PubMed  Google Scholar 

  • Ruggiero A, Anwar M, Kim J, Sica L, Gootman N, Gootman M (1997) Induction of c-fos gene expression by spinal cord transection in the rat. Brain Res 763:21–29

    Article  PubMed  CAS  Google Scholar 

  • Ryan D, Drysdale J, Lafourcade C, Pertwee G, Platt B (2009) Cannabidiol targets mitochondria to regulate intracellular Ca2+ levels. J Neurosci 29:2053–2063

    Article  PubMed  CAS  Google Scholar 

  • Scuderi C, Filippis D, Iuvone T, Blasio A, Steardo A, Esposito G (2009) Cannabidiol in medicine: a review of its therapeutic potential in CNS disorders. Phytother Res 23:597–602

    Article  PubMed  CAS  Google Scholar 

  • Sharma S, Westman J, Olsson Y, Alm P (1996) Involvement of nitric oxide in acute spinal cord injury: an immunocytochemical study using light and electron microscopy in the rat. Neurosci Res 24:373–384

    Article  PubMed  CAS  Google Scholar 

  • Tator CH (1995) Update on the pathophysiology and pathology of acute spinal cord injury. Brain Pathol 5(4):407–413

    Article  PubMed  CAS  Google Scholar 

  • Tator CH (1996) Experimental and clinical studies of the pathophysiology and management of acute spinal cord injury. J Spinal Cord Med 19(4):206–214

    PubMed  CAS  Google Scholar 

  • Tator CH (1998) Biology of neurological recovery and functional restoration after spinal cord injury. Neurosurgery 42(4):696–707

    Article  PubMed  CAS  Google Scholar 

  • Thomas A, Baillie L, Phillips M, Razdan K, Ross A, Pertwee G (2007) Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 150:613–623

    Article  PubMed  CAS  Google Scholar 

  • Wada S, Yone K, Ishidou Y, Nagamine T, Nakahara S, Niiyama T, Sakou T (1999) Apoptosis following spinal cord injury in rats and preventative effect of N-methyl-d-aspartate receptor antagonist. J Neurosurg 91:S98–S104

    Google Scholar 

  • Watson C, Paxinos G, Kayalioglu G (2009) The spinal cord. A Christopher and Dana Reeve Foundantion text and atlas. Academic Press, San Diego

    Google Scholar 

  • Webb A, Ngan S, Fowler D (2010) Spinal cord injury I: a synopsis of the basic science. Can Vet J 51:485–492

    PubMed  Google Scholar 

  • Wisdom R (1999) AP-1: one switch for many signals. Exp Cell Res 253:180–185

    Article  PubMed  CAS  Google Scholar 

  • Xu M, Guénard V, Kleitman N, Aebischer P, Bunge B (1995) A combination of BDNF and NT-3 promotes supraspinal axonal regeneration into Schwann cell grafts in adult rat thoracic spinal cord. Exp Neurol 134:261–272

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Kim M, Ahmed H, Xu J, Yan P, Xu M, Hsu Y (2001) Glucocorticoid receptor-mediated suppression of activator protein-1 activation and matrix metalloproteinase expression after spinal cord injury. J Neurosci 1:92–97

    Google Scholar 

  • Yang K, Mu S, Xue J, Whitson J, Salminen A, Dixon E, Liu K, Hayes L (1994) Increased expression of c-fos mRNA and AP-1 transcription factors after cortical impact injury in rats. Brain Res 664:141–147

    Article  PubMed  CAS  Google Scholar 

  • Zhang ZF, Liao WH, Yang QF, Li HY, Wu YM, Zhou XF (2003) Protective effects of adenoviral cardiotrophin-1 gene transfer on rubrospinal neurons after spinal cord injury in adult rats. Neurotox Res 5:539–548

    Article  PubMed  Google Scholar 

  • Zuardi A, Crippa J, Hallak J, Moreira F, Guimarães FS (2006) Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug. Braz J Med Biol Res 39:421–429

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

Authors are indebted to C. A da-Silva and V. F. Garcez for their skillful assistance during performance of this study. This article was a part of the Master in Sciences Thesis of Marcelo Kwiatkoski, FMRP, Physiology—USP. Financial support: CAPES, FAPESP, and CNPQ.

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  1. Department of Physiology, Faculty of Medicine of Ribeirão Preto (FMRP), Universidade de São Paulo, Ribeirão Preto, SP, 14049-904, Brazil

    Marcelo Kwiatkoski & Elaine Del-Bel

  2. Department MEF-Physiology, School of Odontology, Universidade de São Paulo, Ribeirão Preto, SP, 14049-904, Brazil

    Marcelo Kwiatkoski & Elaine Del-Bel

  3. Department of Pharmacology, Faculty of Medicine of Ribeirão Preto (FMRP), University of São Paulo, Ribeirão Preto, SP, 14049-904, Brazil

    Francisco Silveira Guimarães

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  1. Marcelo Kwiatkoski
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Correspondence to Elaine Del-Bel.

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Kwiatkoski, M., Guimarães, F.S. & Del-Bel, E. Cannabidiol-treated Rats Exhibited Higher Motor Score After Cryogenic Spinal Cord Injury. Neurotox Res 21, 271–280 (2012). https://doi.org/10.1007/s12640-011-9273-8

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